Platelets occur in whole blood and are an integral component of thrombus formation and blood coagulation. Glycoprotein IIb-IIIa, a member of the integrin superfamily, is found on the platelet surface and participates in platelet function by interacting with proteins such as fibrinogen, which contain the amino acid sequence Arg-Gly-Asp. Various factors activate the GPIIb-IIIa receptor allowing interaction with fibrinogen and stimulating platelet aggregation and thrombus formation. A compound which blocks the interaction of GPIIb-IIIa with Arg-Gly-Asp containing peptides such as fibrinogen would antagonize platelet activation by any stimulus and would be an important anti-thrombotic agent.
Many disease states are characterized by blood vessel occlusion due to thrombus formation. Some of these thrombotic diseases are myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion and coronary artery reocclusion following angioplasty. Patients whose blood flows over artificial surfaces are also at risk for thrombus formation. An agent which blocks platelet aggregation by inhibiting fibrinogen binding to the GPIIb-IIIa receptor should be useful in these hyperthrombotic states.
This invention describes such an agent which is a peptide of varying length and contains the Arg-Gly-Asp sequence or an analog thereof and is conformationally restrained by cyclization of an amino acid residue side-chain onto a backbone (CH.sub.2 NH) amide bond replacement. The cyclization strategy described allows the preparation of a linear peptide of varying length containing a conformational restraint at the important Arg-Gly-Asp sequence. A combination of varying peptide length and localized conformational restraint will provide peptides with high platelet aggregation inhibiting activity.